title: Assessment of the early effects of 5,6-dimethylxanthenone-4-acetic acid using macromolecular contrast media-enhanced magnetic resonance imaging: ectopic versus orthotopic tumors.
abstract: OBJECTIVE
  To investigate the early effects of a vascular disrupting agent (VDA) in ectopic and orthotopic tumors by using macromolecular contrast media (MMCM)-enhanced magnetic resonance imaging (MMCM-MRI).
  
  
  METHODS
  The MMCM-MRI of ectopic and orthotopic MCA205 murine fibrosarcomas was performed using the intravascular contrast agent albumin-(gadopentetate dimeglumine)(35). Change in longitudinal relaxation rate (DeltaR1) was measured 24 hours after treatment with 5,6-dimethylxanthenone-4-acetic acid (DMXAA; 30 mg/kg) and used to compute tumor vascular volume and permeability. Correlative histologic and immunohistochemical evaluation was carried out, along with measurement of tumor necrosis factor alpha and vascular endothelial growth factor levels in whole tumor extracts using the enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Orthotopic tumors showed higher vascular volume (p < 0.05) than ectopic tumors before treatment. Twenty-four hours after DMXAA treatment, a significant (p < 0.0001), but differential, decrease in DeltaR1 (70% in ectopic and 50% in orthotopic tumors) was observed compared with baseline estimates. Consistent with this observation, greater levels of tumor necrosis factor alpha, an important mediator of the antivascular activity of DMXAA, were measured in ectopic tumors 3 hours posttreatment compared with orthotopic tumors (p < 0.05). Immunohistochemical (CD31) and histologic (hematoxylin and eosin) sections of ectopic and orthotopic tumors showed highly tumor-selective vascular damage after treatment with the presence of viable surrounding normal tissue.
  
  
  CONCLUSIONS
  The MMCM-MRI provided early quantitative estimates of change in tumor perfusion after VDA treatment that showed good correlation with cytokine induction. Differences in the response of ectopic and orthotopic tumors highlight the influence of the host microenvironment in modulating the activity of VDAs.
authors.affiliation: Preclinical Imaging Resource, Cancer Cell Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. mukund.seshadri@roswellpark.org
authors.forename: Mukund
authors.initials: M
authors.lastname: Seshadri
authors.forename: David A
authors.initials: DA
authors.lastname: Bellnier
authors.forename: Richard T
authors.initials: RT
authors.lastname: Cheney
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D003287:Contrast Media; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000473:pathology*; D007089:Image Enhancement / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology*; D016896:Treatment Outcome; D044004:Xanthones / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D003287:Contrast Media; D044004:Xanthones; C066668:vadimezan